Anticoagulant, amide of 3, 3&#39;-carboxy-methylene bis



Patented June 24, 1952 ANTICOAGULANT, AMIDE F 3,3 -CARBOXY- METHYLENEBIS l-HYDROXYCOUMARIN Joseph J. Lovas, Ridgewood, N. Y., assignor toSpecific Pharmaceuticals, Inc., New York, N. Y., a corporation of NewYork No Drawing. Application June 3, 1950, Serial No. 166,070

Claims.

3,3-methylenebis (4-hydroxycoumarin) O O I H H H g 3,3-methlenebis(2,4-diketo-chroman) The said patent also describes esters of the enolform made by reacting the compound with anhydrides or acid halides.

The compound 3,3'-methylenebis (-hydroxycoumarin) is well known underthe trade name Dicoumarol, and has been investigated extensively. It isan anti-coagulant for oral use, but has two important disadvantages. Thefirst is that the onset of the anti-coagulant action is delayed afteroral administration usually for some 12 to 48 hours. This delay isundesirable in conditions requiring immediate effective treatment. Thesecond disadvantage is the persistent and protracted anti-coagulanteffect in the body after withholding administration of the drug. In manycases dangerously low prothrombin levels persist to such an extent as torequire special measures such as blood transfusion or high dosages ofvitamin K to restore the prothrombin level to normal in order to avoidthe danger of hemorrhage after the therapy has been accomplished.

The esters of the 3,3-methylenebis (4-hy- I droxycoumarin), according tosaid Patent No.

(Class 260344.6

2,345,635, prolong the action for a greater period of time. The patentalso recognizes that excessive amounts of the esters may producehemorrhage. The esters are indicated as having the same generalanti-coagulant properties as 3,3- methylenebis (4-hydroxycoumarin)namely prophylaxis and treatment in blood circulatory and vasculardisturbances, including thrombosis, embolism, phlebitis, Buergersdisease, etc.

We have found that the amides of 3,3'-carboxymethylenebis(4-hydroxycoumarin) do not possess the disadvantages of3,3'-meth.ylenebis (4-hydroxycoumarin) or the slower acting estersthereof. More particularly, said amides accomplish a rapid lowering ofprothrombin to any desired level, depending upon the dosageadministered. While the reason for this has not been established, itappears likely that the amides may be more rapidly absorbed. Thus theonset of the action is very rapid after administration of the amides.The amides also have a less protracted effect and are accompanied by arapid normalization of the prothrombin level when the drug is withheld,thereby minimizing dangers due to hemorrhage. While the exact reason forthis advantage also is not known, it appears likely that this may be dueto quicker elimination of the amides from the bloodstream.

The novel compounds of m invention have the following general formula,where R and R are hydrogen or a hydrocarbon radical preferably havingnot more than 5 carbon atoms, such as ethyl, propylene, butyl, amyl,etc.

These may exist in the enol or keto form and reference to the latter isintended to include either form alone or in equilibrium.

The amides may be made in accordance with the invention by reacting anester of 3,3'-carboxymethylenebis (4-hydroxycoumarin) with an ammoniacalcompound, i.e., ammonia or an amine as described hereinafter.Alternatively, the amides may be prepared by reacting a lactone of3,3'-carboxymethy1enebis l-hydroxycoumarin) with the ammoniacal compoundas described in copending application, Serial No. 142,936, filedFebruary '7, 1950, and also described more particularly hereinafter.

Example I As described in said copending application, the lactone of3,3-carboxymethylenebis (4-hydroxycoumarin) may be made by reacting theabove carboxy compound with a dehydrating agent such as. an acid halideor an acid anhydride.

In accordance with an illustrative embodiment, 4.2 grams of3,3-carboxymethylenebis (4- hydroxycoumarin) was added to and dissolvedin 40 cc. of thionyl chloride. (SOQl'zlJ The 3,3 carboxymethylenebis (4hydroxycoumarin) soluble in the thionyl chloride. and. an excess of thelatter can be used as a reaction medium as. Well as a reactioncomponent. The mixture was: heated and refluxed for eight minutesfollowing which the solution was cooled anda crystallinethemanufacturer. i that the compound has two important disadvan solid wasfiltered from the solution and washed- As an alternative method of?preparing the lactone, a mixtureofj 0.2; grams of 3,3.-carboxymethylenebis (4- hydroxycournarin). and cc. of glacial aceticacid was heated to reflux; Ozl cc. of acetic a hydride was added to thesolution and the heating was continued for five. minutes; They notmixture. was filteredand the. precipitate was washed with ethanol. Theyield was 0.1 gram, M'. P..3 with decomposition.

In preparing the simple amide in accordance with my invention, 1.8 gramsof the lactone- (p re: pared as described above using. thionyl chloride)was dissolved in 10' cc. of concentrated (28% aqueous ammonia. Thesolution was permitted to stand at room temperature for about/one hourfollowing which the product was precipitated by; acidifying with dilutesulfuric acid. It was washed with water and dried. The yield of thecrude material was 1,8 grams having a melting point of 205 to 210 C.with decomposition. After recrystallization from acetone, the productweighed 1.5 grams and had a melting point of 210 to 215 C. with,decomposition. It is thought to have the. following formula:

This amide may be. compared, with 3, 3f-meth ylenebisl-hydroxycoumarin)... This latter compound, according to Patent No.2,345,635, and its manufacturer under the. name Dicoumarol, decreasesthe prothrombin concentration of the blood, The compound is intended forthe pro: phylaxis and treatment of intravascular clotting; inpostoperative, post-traumatic and postinfectious thrombophlebitis;pulmonary embolism;

acute embolic or thrombotic occlusion of peripheral arteries; recurrentidiopathic thrombophlebitis. It retards intravascular clotting andpropagation of the thrombus but has not been shown to resolve formedthrombi or to increase the blood supplyto infarcted areas. After alatent period offrom 24 to 48 hours, the prothrombin time slowlyincreases to a maximum in 3 to 5 days and remains increased from 2 to 19days after thecessation of therapy.

These properti'esfof 3,3-methylenebis (4-11 droxycoumarin) are pointedout in Patent No. 2,482,510, and are; included in the warnings of Itwill be seen, therefore,

tages. The. fiirst is the delayed onset (l to 2 days} of theanti-coagulant action, and the long time necessary to reach the maximumeffect (8 to 5 days). This delay is undesirable in conditions requiringimmediate effective treatment. The second disadvantage. is. thepersistent and protracted. anti-coagulant effect. inthe body afterdiscontinuing; the administration. of; the drug (2 to 10 days). For thisreason. strict precautions are to be taken in order; to avoidsevere anddangerous action. The effects. are, cumulative and over-dosage may causesevere hemorrhage. In many cases. dangerous prothrombin levels persistafter; use of 3,3'-meth-ylenebis.-(4-hydroxyccumarin); to. such anextent. following administration of the drug; as torequire bloodtransfusions or high. dosages of vitamin. K to; restore. the prothrombinlevel to normal afterthe therapy has been accomplishe The amides: donot. possess the disadvantages of the3,3-methylenebis-(4-hydroxycoumarin). In contrast with the slow onset,the long time to reach the maximum effect and persistentafter eifects,the amides, accomplish a more rapid de- 7 crease of the prothrombinconcentration of the.

blood apparently due to a morerapid absorption. Thus, the onset of theaction is very rapid after the administration of. the. amides.Furthermore, the latter have a less protracted effect and areaccompanied by a rapid return of the prothrombin level to normal whenthe administration of the drug is discontinued,v apparently due to aquicker elimination of the. compound. A comparison of the amidedescribed in xample II with 3,3- methylenebis-(4-hydroxycoumarin) isshown in The. ethyl amide, of 3,it" carboxymethylenebis-(-hydroxycoumarinl, having. the formula:

I H- -"CZH5 (E C. =Q QHs-H. I 0:0 0:0

was prepared from 3 3'-carboxymethylenebis i-hydroxyeoumarim which canbe made by the condensation of 4-hydroxycoumarin and glyoxylic acid(OHC--COH) in a manner analogous to the condensation of3,3'-methylenebis (l-hydroxycoumarin) with formaldehyde. The 3,3-carboxymethylenebis (4 -hydroxycoumarin) is converted to its ester byreaction with an alcohol and by refluxing for 6-10 hours with aanhydrous alcoholic solution of H01. The alcohol is then distilled offand the residue crystallized from acetone.

The ester is then converted to the corresponding ethyl amide followingthe customary procedures for conversion with ethyl amine as follows:

One part of the ethyl ester is refluxed for 8 hours with 5 parts of a70% solution of ethyl amine. The solution is acidified to a pH of 3-4and the precipitate i filtered off. This precipitate is thenrecrystallized from acetone.

The ethyl amide of 3,3-carboxymethylenebis (4-hydroxycoumarin) is awhite crystalline solid. When the solid is finely ground it melts at 203to 204 C. with decomposition. It has been observed that when a meltingpoint is taken of the crystalline material before grinding, it melts ashigh as 215 to 216 C. with decomposition. It is soluble in sodiumcarbonate and bases of the same or greater strength, insoluble in dilutemineral acids and insoluble in water. It i intended for oraladministration, and for this rea- Butylamide of 3,3- m 1 Actioncarboxymethylenebisyene (4 hydroxycoumarm) (4-hydroxycoumarm) Onset ofaction 6 hours in all cases 24 to 48 hours. Maximum action Mo 15 hoursinama- 3 to 5 days.

ea jority of cases.

Return to initial value. 24 hours inamajor- 2 to 10 days after ity ofcases, 36 administration. hours in all cases after administration.

Example IV The diethylamide of 3,3-carboxymethylenebis(4-hydroxycoumarin) was prepared by dissolving 2 grams of the lactone(made with acetic anhydride in accordance with Example I) in a solutionof 5 cc. of diethylamine and 5 cc. of water.

After standing at room temperature for one hour the product wasprecipitated with an excess of hydrochloric acid and washed with water.The compound was then dried at room temperature and recrystallized fromacetone. The yield was 1.4 grams having a melting point of 148 withdecomposition.

A comparison of the action of this diethylamide with3,3'-methylenebis-(4-hydroxycouma- Son may be compounded in tab1ets rin)is shown in the following table:

Controlled experiments have shown that when administering similaramounts of the ethyl amide ylamide of as 3 ymeth yleneblsabove describedand the 3,3-methyleneb1s (4-hy- (4-hydroxycoumarin) droxycoumarin), thereturn of the prothrombin time to normal is quicker in cases treatedwith o t f fi shouts 24m 48 the said ethyl amide than in those treatedwith gg g g action 0151mm Holidays- 'metbylenebls f hydroxycoumann)-Returntbinitialvalua 36 hours afteradmin- 2 to 10 days after T1115 15shown in the following table: lstratwnadministration.

Percent Normal Prothmmbin Tjme- 40 Other amides may be prepared inaccordance with my invention as indicated generally here- 1m 4 1 7 1 91mm in, and have the same uses as 3,3'-methylenebis-(4-hydroxycoumarin), but with the advantages d f I Percent PercentPercegt Percengs 0f quicker onset of the effect and a less protrac- Ethlami e 0 3,3 -car- 20 60 0 bofiymethylenebis tlve action as explainedherein. i fi l ah 40 10 5 r I clalm' 3, -me yene is yo droxycoumarin) 1.Amides of 3,3 carboxymethylenebis (4 by Thus it will be seen from aconsideration of the first column at 24 hours, the same amount of saidethyl amide has reduced the prothombin level to a greater extent, andfrom the other columns that the effect wears off much more rapidly.

Other amides may be made following the same general procedure and usingammonia or the corresponding amine. For example, other amides may beprepared by reacting ammonia, butyl amine, amyl amine, diethyl amine,etc., with the ethyl ester or other esters as the starting material.

Ezrample III The butylamide of 3,3'-carboxymethylenebis(l-hydroxycoumarin) was prepared by dissolving 5 grams of the lactone(made with thionyl chloride in accordance with Example I) in a solutionof 25 cc. of butyl amine and 25 cc. of water, and permitted to stand atroom temperature. An excess of hydrochloric acid was then added, and theoily precipitate crystallized on standing. The precipitate was filtered,washed with water, dried at room temperature and recrystallized fromacetone. The yield was 4.45 grams having a melting point of 202 C. withdecomposition.

A comparison of the action of this butylamide droxycoumarin) of thefollowing general formula:

3. An amide of 3,3-carboxymethylenebis (4- hydroxycoumarin) of thefollowing formula:

0 11-N o,11, o t t=o t V anzide or qxbszxym h leneb hydroxycoumarin)ojtheiollowipg formula 5. amide f- 3,3f-carboxymethylenebis (4-hydroxycoumarin) of; the following formula:

8 methy enebls. -h dr y oum w r ed th. ammqnie- The metholdi f mak ng; ecom u f elaimflin whioh the ethyl ester of 3',3'-carboxymethyl neb srhydrq ume in is acted with ethyl amine.

9. The method of making the compound of, claim L in which the ethylester of 3,3'-Vcarboxymethylenebis (4-hydroxycoumarin) is reacted hiethy amine.

ihe meth d, o ma in the co n o c1 a,in 1,5 v in which theethyl ester 0 f3,3-cerboxymethylenebis (-hydroxycoumarin) is reacted with: b utylamine.

' JOSEETI-I J. LQVAS.

EEE PENQES QIT D The following reiepencesl are. of record in the filehis. pa t:

UNITED STATES. PATENTS

1. AMIDES OF 3,3'' -CARBOXYMETHYLENEBIS (4-HYDROXYCOUMARIN) OF THEFOLLOWING GENERAL FORMULA: